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However these effects appear to not be due to a modulation of aging, but rather are related to aging-independent drug effects.

A drug that has shown potential to increase longevity in mice duplicated the feat in another group but had little effect on age-related physical and behavioral changes, German investigators reported.

Consistent with results initially reported 4 years ago, mice treated with rapamycin lived significantly longer than did animals treated with a placebo. Rapamycin was associated with improvement in a few neurobehavioral and laboratory outcomes, but the same changes occurred in mice of all ages, not just the older animals.

Age-related changes in tissues and organ systems were essentially unaffected, Dan Ehninger, MD, of the German Center for Neurodegenerative Diseases in Bonn, and coauthors reported in the August issue of the Journal of Clinical Investigation.

"While rapamycin did extend lifespan, it ameliorated few studied aging phenotypes," the authors concluded. "A subset of aging traits appeared to be rescued by rapamycin. Rapamycin, however, had similar effects on many of these traits in young animals, indicating that these effects were not due to a modulation of aging but rather related to aging-independent drug effects.

To date rapamycin is the only FDA-approved drug that has demonstrated the ability to extend longevity. The use has substantial preclinical rationale, as the target of rapamycin (mTOR) has been shown to play a role in regulation of longevity in models, in addition to mice. However, extended longevity does not equate to effects on aging, the authors noted.

The lifespan-extending effects of rapamycin could reflect an effect on life-limiting pathologies, such as cancer, and rapamycin has antineoplastic properties. Moreover, cancers are the leading cause of death in many mouse strains, they continued. Alternatively, rapamycin's anticancer activity could represent just one aspect of a more generalized effect on aging.

Whether inhibition of mTOR slows aging and, by extension, whether rapamycin affects agent dependent functional and structural changes remains unknown. To examine the issue, Ehninger and colleagues administered rapamycin or vehicle to male mice and then evaluated the effects on a battery of neurobehavioral, functional, laboratory, and histologic tests.

The study included three groups of mice that began treatment (rapamycin or control) at different ages: young adulthood (~4 months), midlife (~13 months), and late in life (20 to 22 months). Treatment started 1 year before evaluations began.

In line with previously reported findings, animals in all three groups lived significantly longer with rapamycin (P=0.0326).

In contrast to the longevity findings, effects on most of the age-related phenotypes assessed were not affected by chronic rapamycin treatment. With respect to behavior and cognition, rapamycin-treated animals showed improvement in two of six outcomes.

Evaluation of major organ systems and laboratory parameters showed a similar pattern of improvement in a few outcomes and no effect on most of them. That included the cardiovascular system, liver, endocrine organs, metabolic outcomes, immune system, clinical chemistry, hematology, and cancers and precancerous lesions.

Rapamycin had no effect on a majority of behavioral and cognitive outcomes, muscle function and strength, eye and vision outcomes, and most cardiovascular parameters. Additionally, no effect was observed for hepatic aging, kidney aging, age-related metabolic changes, immune-system changes, and DNA damage.

The results were further muddled by observations of similar effects of rapamycin in animals from different age groups. Old and younger mice alike derived the same behavioral and cognitive benefits and had evidence of favorable effects on most laboratory and histologic parameters for which all age groups were evaluated.

The author of an accompanying editorial compared the results with the fate of the mythological Tithonus, on whom Zeus bestowed immortality but not eternal youth. Consequently, Tithonus spent most of his years in a room by himself where he "babbles endlessly, and no more has strength at all."

"[The authors] found that the vast majority of parameters they measured were not significantly altered by rapamycin, including vision, hearing, and cardiac and skeletal muscle function, all of which are important to quality of life," wrote Arlan Richardson, PhD, of the University of Texas Health Science Center at San Antonio.

"The increase in the severity and number of diseases is a hallmark of aging," he added. "Therefore, an important criterion for evaluating whether a manipulation increases lifespan by delaying aging is the appearance and severity of pathological lesions and disease."

Nonetheless, the data support the "feasibility of clinical trials to study the efficacy of rapamycin in treating diseases of the elderly," Richardson concluded.

The results were somewhat surprising, said Charles Mobbs, PhD, of Mount Sinai Medical Center in New York City. Even so, he echoed Richardson's sentiments.

"I think we all agree that rapamycin is pretty much ready for prime-time use in clinical trials for age-related impairment," Mobbs told MedPage Today.

"I think most of us are thinking along the lines right now of clinical trials for Alzheimer's disease, because there is really not a treatment for Alzheimer's that is effective," he added.

The authors had no relevant disclosures.

Richardson is a stockholder of Rapamycin Holdings.

Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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